Classical versus molecular genetics

Molecular

As an artist, I always found variations in animal coloration fascinating, but I fell in love with coat color genetics in 1989 when I purchased a copy of Horse Color (1983) by Dr. Phillip Sponenberg and Bonnie Beaver. The book contained what seemed at the time to be countless color variations and a structure for categorizing them. I read the book cover to cover, and then set out to find as many of the referenced books and papers that appeared in the bibliography in the back. The whole system seemed so logical, and the basic framework fairly easy to understand.

HorseColor183
One of the pages of color plates from my very worn copy of Horse Color. It is a good thing that eyeballs do not absorb printing ink, or this page would have ended up blank years ago!

Because it is in my nature to share information, it was not long before I was writing about horse color with the intention of teaching others that same framework. And that was how I usually presented the subject: “This is pretty simple.” I could explain the concept of base colors–black, chestnut and bay/brown–and then the modifiers that altered those colors, either by diluting the color itself, or adding white hairs, or covering them with a white pattern. All of those were governed by the rules of genetic inheritance most of us learned in high school biology, when we used Punnett squares to map out the ratios of green and yellow pea pods.  Those ratios would tell us if something was dominant or recessive, or incompletely dominant, or perhaps a homozygous lethal. All that was needed was to tie that knowledge to an eye for the nuances of shade and pattern, and you were set!

Using this approach, I could give an hour-long presentation without using scientific terms like allele or epistasis. Instead I used a system that relied on visual understanding, because I found that many non-scientists would shut down if the initial information was abstract or overly technical. Most of the questions I encountered had pretty straight-forward answers, so this tended to work well. It was easy enough to expand on the basic concepts with technical information once someone was more comfortable with the subject. But somewhere along the way, explaining horse color became a lot more complicated. Over time, I found that even the most basic questions required increasingly more technical answers.

OldSlides2
Cycling through the same set of images, each showing the effect of a given modifier on each of the base colors, was one of the most effective ways to communicate the concept of modifiers. (It could be argued that my use of Comic Sans was perhaps less effective.)

So what changed? Why has color genetics become so complex and so much more technical?

The answer is that there has been a change in the field of genetics. Mendelian genetics, which is also known as classical genetics, predates the advent of molecular biology. The huge leaps in our understanding of coat color in mammals–horses included–come from advances in molecular biology. When horse color research relied on classical genetics, it was pretty easy to explain the subject in simple terms; after all, the original discoveries were made before even the most basic concepts about sexual reproduction were understood. But the science has advanced far past that point, making it not only possible to find the exact, physical mutation in the genetic code, but to understand why that particular change caused the final result that we can see. 

The albino Dobermans are a good example of this difference. Classical genetics could tell breeders that the trait was recessive, and the visual appearance of the dogs suggested that the dogs carried some form of albinism. Molecular genetics makes it possible to tell what kind of albinism (or dilution, if you prefer) is involved. That makes it possible to test for carriers, but it also allows comparisons with other dilutions to help determine what, if any, detrimental effects might occur because of the mutation. As more is known about the function of the different genes–and each mutation found adds to that body of understanding–it becomes easier to predict what might be directly caused by the change, what might be linked, and what might be unrelated. In horses, this kind of research determined that Multiple Congenital Ocular Anomalies (MCOA), formerly known as Anterior Segment Dysgenesis (ASD), was “tightly linked” to the silver dilution, and that homozygous silvers were at greater risk for eye defects regardless of their breed.

Another good contrast between classical genetics and molecular genetics is the prediction of lethality. In a comment from the last post, a reader asked about the belief that some forms of Dominant White were lethal in their homozygous form. In classical genetics, crosses that produced early lethals (that is, lost pregnancies rather than offspring that did not survive long) were determined by the absence of true-breeding individuals, and a ratio that indicated that one portion of the expected outcome was missing (2:1 instead of 3:1). While those factors are still considered, knowing what role each gene plays in the development of the organism allows researchers to predict outcomes in a way that just looking at production ratios cannot. If the gene is responsible for task A, B and C during development, and if shutting its function down at point X ends that process before reaching C, and if C is necessary for life, then it can be assumed that without a normal copy of the same gene (ie., if the animal is homozygous for that mutation) the resulting offspring is non-viable. That is why some recent studies have suggested that certain crosses might not be viable, even when the mutations themselves are rare enough that there are not statistically significant numbers to assess ratios, and where a lack of true-breeding animals might not be particularly informative.

Lethal
This Punnet Square of Lethal Yellow in mice illustrates how homozygous lethals change the expected ratio from 3:1 to 2:1. Instead of the three yellow (two heterozygous and one homozygous) and one white, the result is two yellow to one white. 

For breeders, this level of understanding holds a lot of promise for the future, because it makes it possible to analyze the connection–or lack of connection–between a color and undesirable traits. In the past, defects have been tied to colors, often using nothing more than rumor or supposition. It was not unusual to see a superficial similarity, like white patches or lighter eyes, used to suggest that a given color was susceptible to the same defects. This is how a diluted dog becomes an “albino” carrying something that is “a defect in all species”. Molecular genetics offers the opportunity to examine the actual cause for the reduction in pigment, and a means of determining just exactly what other problems, if any, this alteration might create. Yes, this does mean that more often the answer to questions about color will be, “It is complicated,” rather than “It really is pretty simple.” But knowing the true nature of a given mutation, and being able to identify it, gives breeders more control when it comes to obtaining, or avoiding, certain colors. And instead of culling all suspect animals, and losing whatever else they might have to contribute to their breed, breeders can make more informed selections whatever their goals are in terms of color. Seen in that light, the increased complexity of modern genetics seems a small price to pay.

(Punnet Square graphics courtesy of Wikimedia Commons, with apologies to my rodent-loving readers. Molecular graphic courtesy of the U.S. National Library of Medicine.)

2 Responses to Classical versus molecular genetics

  1. Kristina Pry January 28, 2014 at 9:34 pm #

    In the book page image, the horse in the bottom right corner is listed as OO. Were max white horses originally thought to be homozygous overo?

    • equinetapestry January 29, 2014 at 10:31 am #

      No, when the book was written, Bowling had not yet published her paper disproving the theory that “overo” was recessive. So the notation for overo was O (normal) and o (carrier). He was indicating that the colt was a tobiano, but not carrying overo. Or at least, not that kind, because you’ll note that he describes the colt as an overo-tobiano.